Autor: PJW Venables, MA, MB BChir, MD, FRCP

Editor de sección: James R. O'Dell, MD

Editor adjunto: Paul L Romain, MD

Divulgaciones del colaborador

Todos los temas se actualizan a medida que se dispone de nueva evidencia y se completa nuestro proceso de revisión por
pares .

Revisión de literatura vigente hasta:  septiembre de 2020. | Este tema se actualizó por última vez:  30 de octubre de
2019.

INTRODUCCIÓN

La artritis reumatoide (AR) es un trastorno inflamatorio sistémico crónico de etiología desconocida

que afecta principalmente a las articulaciones sinoviales. La artritis es típicamente simétrica y
generalmente conduce, si no se controla, a la destrucción de las articulaciones debido a la erosión
del cartílago y el hueso, lo que causa deformidades articulares. La enfermedad generalmente
progresa desde la periferia a las articulaciones más proximales y da como resultado una
discapacidad locomotora significativa dentro de los 10 a 20 años en pacientes que no responden por
completo al tratamiento.

Aquí se revisan las principales características clínicas de la AR, incluidas las manifestaciones
articulares. Las características sistémicas y no articulares y el diagnóstico y diagnóstico diferencial de
la AR se discuten en detalle por separado. (Consulte "Descripción general de las manifestaciones
sistémicas y no articulares de la artritis reumatoide" y "Diagnóstico y diagnóstico diferencial de la
artritis reumatoide" ).

PRESENTACIÓN CLÍNICA INICIAL

La artritis reumatoide (AR) se presenta más típicamente como enfermedad poliarticular y con un
inicio gradual, pero algunos pacientes pueden presentar un inicio agudo con afectación articular
intermitente o migratoria o con enfermedad monoarticular. (Consulte 'AR' clásica 'típica' a
continuación y 'Reumatismo palindrómico' a continuación y 'Monoartritis' a continuación).

Los síntomas de la artritis pueden afectar la capacidad del paciente para realizar las actividades de la
vida diaria (p. Ej., Caminar, subir escaleras, vestirse, usar el baño, levantarse de una silla, abrir
frascos, puertas, mecanografiar) y su capacidad para hacer su trabajo. .

Los síntomas sistémicos también pueden estar presentes en estos pacientes; hasta en un tercio de
los pacientes, el inicio agudo de la poliartritis se asocia con mialgia prominente, fatiga, febrícula,
pérdida de peso y depresión. Con menor frecuencia, también pueden presentarse manifestaciones
extraarticulares como nódulos o epiescleritis. (Consulte 'Afectación extraarticular' a continuación).

Enfermedad articular
 AR “clásica” típica  :  el inicio de la enfermedad en la AR suele ser insidioso, y los síntomas
predominantes son dolor, rigidez (especialmente rigidez matutina) e hinchazón de muchas
articulaciones [ 1 ]. Por lo general, las articulaciones metacarpofalángicas (MCP) e interfalángicas
proximales (PIP) de los dedos, las articulaciones interfalángicas de los pulgares, las muñecas y las
articulaciones metatarsofalángicas (MTP) de los dedos de los pies son sitios de artritis en las
primeras etapas de la enfermedad. Otras articulaciones sinoviales de las extremidades superiores e
inferiores, como los codos, los hombros, los tobillos y las rodillas, también se ven afectadas con
frecuencia [ 2,3 ].

La rigidez matutina es una característica común de las personas con AR activa; se puede definir como
"lentitud o dificultad para mover las articulaciones al levantarse de la cama o después de permanecer
en una posición demasiado tiempo, lo que involucra a ambos lados del cuerpo y mejora con el
movimiento" [ 4 ]. La rigidez matutina que dura más de una hora refleja una gravedad de la
inflamación articular que rara vez ocurre en enfermedades distintas de la AR, aunque la rigidez
matutina o la rigidez después de un período prolongado de inactividad también se observa en
prácticamente todas las artropatías inflamatorias [ 5 ].

Ocasionalmente, pueden estar presentes características que sugieren polimialgia reumática (PMR)
además de características de AR poliarticular, y algunos pacientes que posteriormente desarrollan AR
pueden presentar PMR típica. Cuando esto ocurre en ausencia de sinovitis clínicamente detectable,
es posible que las características clínicas distintivas de la AR no se desarrollen hasta meses o incluso
años después. (Ver "Manifestaciones clínicas y diagnóstico de polimialgia reumática", sección sobre
"Características clínicas" y "Manifestaciones clínicas y diagnóstico de polimialgia reumática", sección
sobre "Diagnóstico diferencial" ).

Reumatismo palindrómico  :  el inicio de la AR es episódico en unos pocos pacientes, con una o
varias áreas articulares afectadas secuencialmente durante horas o días, alternando con períodos
libres de síntomas que pueden durar de días a meses; este patrón episódico se denomina
"reumatismo palindrómico". Los pacientes con reumatismo palindrómico tienen factores de riesgo
genéticos predisponentes similares a los de los pacientes con una presentación persistente más
típica de AR y exhiben un efecto de dosis similar de transporte de ciertos alelos del antígeno
leucocitario humano (HLA) [ 6 ]. (Ver "Diagnóstico y diagnóstico diferencial de la artritis reumatoide",
sección sobre 'Reumatismo palindrómico' y"Epidemiología, factores de riesgo y posibles causas de la
artritis reumatoide", sección sobre 'Factores de riesgo familiares y genéticos' .)

La proporción de pacientes que presentan reumatismo palindrómico que progresan hasta

desarrollar AR u otra enfermedad bien definida varía entre los estudios. En un estudio de 60
pacientes con reumatismo palindrómico seguidos durante 20 años, 40 (67 por ciento) desarrollaron
AR [ 7 ]. En otro estudio, entre 147 de estos pacientes atendidos en un centro de referencia terciario,
41 fueron finalmente diagnosticados con AR (28 por ciento) y cuatro con otros trastornos (tres con
lupus eritematoso sistémico y uno con síndrome de Behçet) [ 6 ].

La presencia de anticuerpos anti-péptido / proteína citrulinados (ACPA), un hallazgo serológico que

es común en la AR, podría predecir la progresión del reumatismo palindrómico a AR, pero la
evidencia que evalúa esta posibilidad ha sido mixta [ 8 ]. En un estudio, en el que participaron 61
pacientes seguidos durante una media de cinco años y medio, la prueba de ACPA se realizó dentro
de un año de la aparición de los síntomas y los anticuerpos estaban presentes en el 83 por ciento de
los pacientes que progresaron a AR definida, pero solo el 19 por ciento de aquellos cuya enfermedad
no lo hizo [ 9 ]. Sin embargo, en otro estudio, la mayoría de las personas con reumatismo
palindrómico también tenían ACPA, pero no hubo diferencias significativas en la frecuencia de ACPA
entre los pacientes con reumatismo palindrómico persistente y los que posteriormente desarrollaron
AR [ 10]. (Ver "Marcadores biológicos en el diagnóstico y evaluación de la artritis reumatoide", sección
sobre "Anticuerpos anti-péptidos citrulinados" ).

Una respuesta de los pacientes con reumatismo palindrómico a la hidroxicloroquina , que también se
utiliza para el tratamiento de la AR, respalda aún más la posibilidad de que el reumatismo
palindrómico pueda ser una característica de presentación de la AR. El uso de hidroxicloroquina en
estos pacientes también puede reducir el riesgo de progresión a AR. Un estudio retrospectivo de 113
pacientes con reumatismo palindrómico encontró que aquellos que recibieron hidroxicloroquina
tenían un 20% menos de probabilidades de desarrollar una enfermedad reumática crónica [ 11 ].

Monoartritis  :  la artritis persistente de una sola articulación (monoartritis), con frecuencia de
una articulación grande como la muñeca, la rodilla, el hombro, la cadera o el tobillo, puede ser la
única manifestación de AR o puede anunciar la aparición de una enfermedad poliarticular. Puede
haber antecedentes de traumatismo articular como evento inicial aparente. El intervalo entre la
monoartritis y la poliartritis puede extenderse de días a varias semanas en pacientes cuya
enfermedad progresa. Hasta que se desarrolle la poliartritis, el enfoque para estos pacientes es el de
cualquier paciente con artritis monoarticular. (Ver "Monoartritis en adultos: etiología y evaluación" ).

Afectación extraarticular  :  una proporción de pacientes se queja de una constelación de síntomas
no articulares persistentes, que pueden ser anteriores al inicio de la poliartritis en muchos meses;
estos incluyen dolor generalizado, rigidez, síntomas del síndrome del túnel carpiano bilateral,
pérdida de peso, depresión y fatiga (la última simulación del síndrome de fatiga crónica [SFC],
también conocido como encefalomielitis miálgica / síndrome de fatiga crónica [EM / SFC]).

La afectación del sistema musculoesquelético además de las articulaciones (p. Ej., Huesos y
músculos) y de órganos no articulares (p. Ej., Piel, ojos, pulmones, corazón y otros) ocurre en
aproximadamente el 40 por ciento de los pacientes con artritis reumatoide (AR) durante el curso de
la enfermedad. Además, los pacientes rara vez pueden presentar enfermedad extraarticular en
ausencia de artritis clínica.

The systemic and extraarticular manifestations of RA are discussed in detail separately. (See
'Symptoms and physical findings' below and "Overview of the systemic and nonarticular
manifestations of rheumatoid arthritis".)

SYMPTOMS AND PHYSICAL FINDINGS

Joint pain and swelling, especially of the small joints of the hands, wrist, and forefoot are common,
along with morning stiffness and decreased grip strength, although all peripheral joints and, to a
lesser degree, the more proximal joints of the extremities can be affected. The axial skeleton is
usually spared, other than the cervical spine, where severe disease may cause serious neurologic
compromise, generally in patients with longstanding disease. Patients with poorly controlled disease
typically experience progressive joint damage, which may result in significant joint deformities and
functional impairment (see 'Physical findings of joint inflammation' below and 'Distribution of
involved joints' below and 'Upper extremity' below and 'Lower extremity' below and 'Axial skeleton'
below and 'Cricoarytenoid joint' below). Disease outcome and functional impairment in rheumatoid
arthritis (RA) are reviewed in detail separately. (See "Disease outcome and functional capacity in
rheumatoid arthritis".)

Symptoms and findings of systemic and nonarticular manifestations may include generalized aching,
stiffness, weight loss, depression, and fatigue. Most patients with extraarticular features of RA have
longstanding and severe disease; these features, which are discussed in more detail separately,
include anemia, fatigue, subcutaneous ("rheumatoid") nodules, pleuropericarditis, neuropathy,
episcleritis, scleritis, splenomegaly, Sjögren's syndrome, vasculitis, and others. (See "Overview of the
systemic and nonarticular manifestations of rheumatoid arthritis".)

Physical findings of joint inflammation — The key features of early rheumatoid inflammation are
pain and swelling of the affected joints. Painful inflammation is demonstrated either by local
tenderness from pressure applied on the joint or by pain on moving the joint. Swelling may be due to
synovial hypertrophy or effusion. Synovial thickening is detected by a "boggy" feel to a swollen joint,
and effusion by demonstrating fluctuance. Heat and redness are not prominent features of RA,
although an involved joint is often perceptibly warmer on careful examination. Synovitis of the wrist
may present as carpal tunnel syndrome even in very early disease, when swelling may not be
particularly evident. The characteristic joint deformities are late manifestations of disease that result
from the physical stresses and damage to the local anatomy of involved joints.

Distribution of involved joints — RA eventually affects the peripheral joints in almost all patients.
Involvement of axial and central joints is less common, occurring in 20 to 50 percent of patients; such
joints include the interfacetal and atlantoaxial joints of the neck; the acromioclavicular [12],
sternoclavicular, temporomandibular, and cricoarytenoid joints; and the shoulders and hips. Lumbar
spine facet joint synovitis may occur, but the frequency of such involvement is rare.

Symmetrical involvement of joints is a characteristic feature, although this may be less apparent early
in the disease. The severity of joint disease and consequent deformity is sometimes notably
asymmetrical, an observation that may be attributed to increased structural damage to joints related
to unilateral overuse of a dominant limb, or joint protection of a limb resulting from neurologic
disease. Squeeze tenderness at the metacarpophalangeal (MCP) and metatarsophalangeal (MTP)
joints and palpable synovial thickening at these joints are characteristic of RA.

Upper extremity

Hands — The main signs of disease can often be found in the hands early in the course of RA [13].
Symmetrical effusions and soft tissue swelling around the MCP and proximal interphalangeal (PIP)
joints typically occur. These joints are tender to the touch and exhibit a restricted range of
movement. Reduced grip strength is a sensitive but nonspecific feature of disease activity affecting
the hands and wrists. Palmar erythema may be present (as with any peripheral arthritis).

Occasionally, thickening of the flexor tendons can be detected by palpation of the palm; this finding
is due to synovitis of the tendon sheaths ("tenosynovitis"). Nodules may form along the palmar
tendon sheaths, resulting in the tendon sheath catching (or triggering) and in an inability to fully
extend the finger. The nodules may cause tendon rupture, especially of the extensor pollicis longus
(extensor of the distal interphalangeal [DIP] joint of the thumb).

Other physical signs include:

● Reduced grip strength, which is common, can be a surprisingly sensitive indicator of early
disease, as well as a useful parameter in the evaluation of disease activity and progression.
However, the multiplicity of factors (joint pain, tendon involvement, nerve compression, and
muscle wasting) that contribute to a weak grip makes this assessment rather nonspecific.

● The whole hand may be swollen in very acute RA, with pitting edema over the dorsum giving rise
to the "boxing glove" appearance. The range of movement of involved joints is restricted, and
loss of active flexion may be so severe that the patient is unable to oppose the finger tips to the
palm.

● Between 1 and 5 percent of patients present with carpal tunnel syndrome. Affected patients
develop dysesthesia and muscle weakness of the first three fingers and the radial side of the
fourth finger. A positive Tinel's or Phalen's sign is usually present. (See "Carpal tunnel syndrome:
Clinical manifestations and diagnosis".)

The characteristic joint deformities appear in more established chronic RA. These findings include
ulnar deviation or "ulnar drift", swan neck and Boutonniere deformities of the fingers (
picture 1A-C), and the "bow string" sign (prominence of the tendons in the extensor compartment
of the hand). Occasional patients present with extensor tendon rupture, most commonly affecting
the thumb or little or ring fingers of either hand. The nails and fingertips may show evidence of
digital infarcts in patients with rheumatoid vasculitis. (See "Clinical manifestations and diagnosis of
rheumatoid vasculitis", section on 'Cutaneous vasculitis'.)

Wrists, elbows, and shoulders — All of the upper extremity joints may be involved in RA,
including the wrists, usually early in the disease course, as well as the elbows and shoulders:

● Wrists – The wrist is probably the most common upper extremity joint to be involved other than
the small joints in the hand. Early in the disease there is a loss of extension. Late changes due to
erosive damage lead to volar subluxation and radial drift of the carpus, resulting in increasing
prominence of the ulnar styloid and lateral deviation [14]. Tendon rupture can also occur at the
wrist.

● Elbows – The elbow is frequently affected, with loss of extension (fixed flexion) both in early and
late disease ( image 1). An effusion or synovitis may be detected as a bulge between the head
of the radius and the olecranon. A compressive neuropathy of the ulnar nerve, with dysesthesias
 of the fourth and fifth fingers, can result from elbow synovitis. Olecranon bursitis is also
common. Destruction of the joint may occur due to erosion of cartilage and bone.

The elbow is the most common site for subcutaneous rheumatoid nodules ( picture 2). These
should always be looked and felt for in view of their diagnostic and prognostic importance. (See
"Rheumatoid nodules".)

● Shoulders – The shoulder, being more proximal, tends to be involved later in the disease. A
prospective study performed prior to the widespread availability of biologic agents assessed
shoulder involvement over time in 74 patients with RA [15]. At 15 years, 55 percent had
developed radiographic evidence of erosive glenohumeral joint disease [15]. The most common
site for erosions was the superolateral aspect of the humerus.

Disease in the glenohumeral joint leads to painful restriction of movement resembling a

capsulitis, and can result in the development of a "frozen" shoulder. This will typically cause pain
at night, when the patient lies on the affected shoulder. Rotator cuff injury is common. Effusions
are relatively rare, but when they occur they may be detected in the anterior glenohumeral joint
as a filling of the depression under the clavicle anterior to the head of the humerus.

Lower extremity — Lower extremity joints are often involved in RA, particularly in the forefoot and
ankles; the knees and hips may also be affected, but hip involvement tends to occur in more severe
or longstanding disease. Synovitis in the knee may predispose to the development of popliteal
(Baker's) cysts.

● Feet and ankles – Foot involvement, especially of the MTP joints, is common in early disease,
with a pattern which mirrors that occurring in the hand.

• Tenderness of the MTP joints may be marked, resulting in the tendency to bear weight on
the heels and hyperextend the toes.

• Erosive damage results in lateral drift of the toes and plantar subluxation of the metatarsal
heads ( picture 3), resulting in "cock-up" deformities. The latter may be palpable as bony
lumps on the sole with associated callosities.

• Involvement of the tarsus and the associated tendon sheaths is also common, leading to
pain on inversion or eversion of the foot and diffuse edema and erythema over the dorsum
of the foot.

• Heel pain may be associated with retrocalcaneal bursitis or tarsal tunnel syndrome, caused
by impingement of the posterior tibial nerve. Tarsal tunnel syndrome is also associated with
paresthesiae of the toes and is important because it can be diagnosed by ultrasound and
treated by local injection or surgical release. (See "Overview of lower extremity peripheral
nerve syndromes", section on 'Tarsal tunnel syndrome'.)

• Arthritis of the ankle can lead to a diffuse swelling around the tibiotalar joints, which may be
red and edematous. These findings may be wrongly attributed to fluid retention or an
infective cellulitis of the skin.
 ● Knees – The knee manifests many changes in RA. Synovial thickening is easily detected at the
knee, often extending around the patella. Effusion is a common feature of knee involvement and
can be elicited by patellar tap. Restriction of movement, particularly flexion, is also a common
physical finding. In addition, ligamentous laxity leading to deformities and quadriceps atrophy is
frequently observed. Erosion of the femoral condyles and tibial plateau can result in either genu
varus or genu valgus.

Patients with RA may develop popliteal (Baker's) cysts, which can be detected by palpation of the
popliteal fossa [16]. Ruptured Baker's cysts extending down the calf are of clinical importance
because they can resemble a deep vein thrombosis or acute thrombophlebitis [17]. A history of
arthritis, morning stiffness, lack of a palpable occluded venous cord, and edema below the
posterior of the knee all suggest a Baker's cyst. Ultrasonography is generally used for the
detection of intact or ruptured Baker's cysts ( image 2A-B), and they can be readily imaged by
magnetic resonance imaging (MRI), although historically a ruptured Baker's cyst was usually
demonstrated using arthrography [18]. (See "Popliteal (Baker's) cyst".)

● Hips – Involvement of the hips typically occurs only in well-established disease. Hip disease is
most frequently manifested as pain in the groin, thigh, or low back, or referred to the knee on
standing or movement. Restriction of movement, detected by "log rolling the leg" or rotation of
the hip, also may be seen. Pain in the lateral thigh suggests trochanteric bursitis. (See "Greater
trochanteric pain syndrome (formerly trochanteric bursitis)".)

Axial skeleton — Cervical spine involvement is relatively common in RA, especially in longstanding

disease, compared with the very infrequent involvement that occurs in the thoracolumbar spine or
sacroiliac joints. Symptoms of pain and stiffness in the neck are the most typical manifestation, but
disease affecting the joints of the cervical spine can be of critical clinical importance, as longstanding
disease may lead to instability and cause symptoms related to subluxation such as neck pain,
stiffness, and radicular pain. If the subluxation is causing spinal cord compression, there may be
signs of long tract involvement such as hyperreflexia or up going toes on Babinski testing. The
clinical manifestations of cervical spine subluxation and the approach to diagnosis and management
are discussed in detail separately. (See "Cervical subluxation in rheumatoid arthritis".)

Involvement of the facet joints of the lumbar spine and occasionally discitis has been reported to
occur in RA, both from radiographic and post-mortem studies [19]. However, in clinical practice, it is
important to exclude common and serious causes of back pain, such as vertebral compression
fractures associated with low bone mass, before attributing back pain to rheumatoid involvement of
the lumbar spine.

Cricoarytenoid joint — Approximately 30 percent of patients with RA have involvement of the

cricoarytenoid joint demonstrated by indirect laryngoscopy, with the prevalence increasing when
advanced imaging techniques are used. As an example, one study from 1984, involving 45 patients
with RA, found laryngeal involvement in 32 percent by laryngoscopy and 54 percent by computed
tomography (CT) [20]; symptoms may include hoarseness and an inspiratory stridor.
LABORATORY FINDINGS

A number of abnormalities are present in the blood and synovial fluid of patients with rheumatoid
arthritis (RA) that reflect the presence of systemic and intraarticular inflammation and the
autoimmune features of the disorder; these include inflammatory joint fluid, anemia of chronic
inflammation, the presence of rheumatoid factors (RF) and anti-citrullinated peptide/protein
antibodies (ACPA), and evidence of an acute phase response that tends to correlate with the degree
of disease activity.

● Synovial fluid – Synovial fluid examination in affected joints usually reveals an inflammatory
effusion, with a leukocyte count typically between 1500 and 25,000/cubic mm characterized by a
predominance of polymorphonuclear cells [21]. Cell counts in excess of 25,000 may occur in very
active disease, but levels over 25,000 should alert the clinician to the increased possibility of
coexisting infection [22,23]. Additional findings in RA synovial fluid are low C3 and C4
complement levels in contrast to higher levels found in the blood. Historically, synovial fluid
glucose levels in RA have been noted to be low relative to simultaneous blood glucose
measurement, but such testing is not useful in clinical practice. (See "Synovial fluid analysis" and
"Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Evaluation for
suspected RA'.)

● Hematologic – Common hematologic abnormalities associated with active disease include

anemia of chronic inflammation, thrombocytosis, and sometimes a mild leukocytosis. There is an
increased risk of lymphoproliferative disease, including non-Hodgkin lymphoma. Felty syndrome,
with neutropenia and splenomegaly is very infrequent. The hematologic features of RA are
described in detail separately. (See "Hematologic manifestations of rheumatoid arthritis" and
"Clinical manifestations and diagnosis of Felty syndrome" and "Large granular lymphocyte
leukemia in rheumatoid arthritis".)

● Autoantibodies – About 75 to 80 percent of patients with RA test positive for RF, ACPA, or both;
patients with RA and such antibodies are defined as having "seropositive RA" and the presence of
the antibodies has diagnostic, therapeutic, and prognostic implications. About a quarter to a
third of patients have antinuclear antibodies as well. These serologic features of RA are reviewed
in detail separately. (See "Biologic markers in the diagnosis and assessment of rheumatoid
arthritis" and "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Serology'
and "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Evaluation for
suspected RA'.)

● Acute phase response – Measures of the acute phase response, including the erythrocyte
sedimentation rate (ESR) and levels of C-reactive protein (CRP), are usually elevated in patients
with active disease, and the degree of elevation in a given patient tends to correlate with disease
activity; however, mild disease activity is sometimes present without such abnormalities. ESR and
CRP in RA and the acute phase response are discussed in more detail separately. (See "Biologic
markers in the diagnosis and assessment of rheumatoid arthritis", section on 'Erythrocyte
 sedimentation rate' and "Biologic markers in the diagnosis and assessment of rheumatoid
arthritis", section on 'C-reactive protein' and "Acute phase reactants".)

IMAGING

Patients with rheumatoid arthritis (RA) develop joint space narrowing and bony erosions, which are
best observed in plain radiographs of the hands and feet (see 'Plain film radiography' below). These
may already be present when first seen by a clinician but more usually become evident over time
with ongoing synovitis beyond the first few months of disease. Erosions of cartilage and bone are
among the cardinal features of RA. However, they can also occur in some other forms of
inflammatory and gouty arthropathy and are therefore not diagnostic of RA in and of themselves.
(See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Differential diagnosis'.)

Magnetic resonance imaging (MRI) studies and ultrasonography are more sensitive than radiography
for the detection of changes resulting from synovitis, but additional research is ongoing to determine
the prognostic importance of changes observed with these studies that are not evident
radiographically. (See 'MRI' below and 'Ultrasonography' below.)

Plain film radiography — Progressive radiographic changes occur in the affected joints of patients
with active disease, including periarticular osteopenia, joint space narrowing, and bone erosions.
Deformities, including joint subluxation, and secondary degenerative changes may occur with an
active disease course.

Plain radiographs are often normal early in disease, and the early changes evident on plain films may
include only soft tissue swelling and periarticular osteopenia ( image 3A-C). To be detected by plain
radiography, erosions must have eroded through the cortex of the bone around the margins of the
joint. In studies done in the late 1980s and early 1990s, erosions in the metacarpophalangeal (MCP) (
image 4A-B) and proximal interphalangeal (PIP) joints ( image 5A-B) were identified by plain
radiography in 15 to 30 percent of patients in the first year of the disease. By the end of the second
year of disease in patients who did not respond to therapy, the cumulative incidence of erosions was
90 percent [24,25]. In some patients, erosions occur first in the ulnar styloid ( image 6A-B) or
metatarsophalangeal (MTP) joints ( image 7A-B). Joint space narrowing may also be present.
Radiographic evidence of joint injury in patients with early RA is often greater in the dominant than
the nondominant hand [26]. Similar asymmetry in joint damage has long been observed in patients
with hemiplegia [27].

With extreme destruction, the severity of erosions may reach a level beyond which further
progression cannot be assessed radiographically, despite the presence of ongoing joint damage [28].

MRI — MRI is a more sensitive technique than plain radiography for identifying bone erosions;
however, the clinical significance of erosions only detected by MRI awaits elucidation [29]. When
radiography and MRI were compared in a group of 55 patients with early arthritis, MRI identified
seven times as many erosions in the MCP and PIP joints than plain radiography [30].
MRI also may detect bone erosions earlier in the course of the disease than is possible with plain
films [31]. As an example, approximately 45 percent of patients with symptoms for only four months
were found to have erosions detected by this method [32]. Decreased signal from the bone marrow
on T1-weighted images and enhancement of the marrow with gadolinium administration is
interpreted as bone marrow edema. The presence of marrow edema on MRI is predictive of later
development of erosive disease [33]. A similarly increased sensitivity of MRI has also been noted for
early RA of the forefoot [34].

It is also possible to identify and estimate the quantity of hypertrophic synovial tissue using MRI. The
presence of MRI-detected synovial proliferation correlates with the later development of bone
erosions [35]. Use of this imaging technique outside of research settings may be hastened by the
development of MRI scanners that are designed specifically for imaging the extremities, but clinical
indications for the use of such techniques remain uncertain [36,37].

Ultrasonography — Ultrasonography is another sensitive alternative imaging technique for

estimating the degree of inflammation and the volume of inflamed tissue. Direct comparison of color
Doppler ultrasonography and contrast-enhanced MRI in one study of 29 patients demonstrated
agreement regarding the presence or absence of inflammation between the two techniques in 75
percent of the joints of the hands and wrists [38]. Both imaging modalities found features of
inflammation in joints that were neither tender nor swollen on physical examination. The clinical
importance of these findings remains to be determined. Ultrasonography can also be used to assess
the MTP joints, which may become affected early in the course of disease [39]. Ultrasound evaluation
for bone erosions and synovitis is described in further detail separately. (See "Musculoskeletal
ultrasonography: Clinical applications", section on 'Joints'.)

CLINICAL COURSE

Rheumatoid arthritis (RA) shows a marked variation of clinical expression in individual patients (
table 1). These differences may be apparent in the number of involved joints and pattern of joint
involvement, fluctuations in disease activity and ability to achieve remission, and the rate of
progression and extent of structural damage. Some patients may have mainly small joints or large
joints affected. A given patient may also have only a few or almost all joints involved. In addition,
extraarticular disease may be prominent in a subset of patients. (See "Overview of the systemic and
nonarticular manifestations of rheumatoid arthritis".)

Patterns of progression — Variation is seen in the course of disease activity and the rapidity of
structural damage to joints [40].

● Most patients show fluctuation of disease activity over periods lasting weeks to months. This
corresponds to an increase or decrease in symptoms of arthritis, a pattern which may recur
throughout the course of the disease.

● Remission has been reported in a small proportion of patients with a well-established diagnosis
of RA, but is very rare, in our experience, without treatment using disease-modifying
antirheumatic drugs (DMARDs) [41,42]. (See 'Remission' below.)
Disease activity versus structural damage — The concept of disease activity is based upon the
state of the underlying inflammatory response and may be distinguished from the destructive
process that leads to irreversible damage of the joint ( table 2):

● Disease activity can (and does) vary. This variation in part reflects the endogenous rhythms of the
disease process but is mainly the result of therapeutic interventions. Thus, periods of
spontaneous exacerbations and quiescence, characterized by an increase (a "flare") or decrease
in symptoms, are modulated by both the beneficial effects of drug therapy and withdrawal of
therapy due to loss of efficacy or side effects. The assessment of disease activity in patients with
RA is described in detail separately. (See "Assessment of rheumatoid arthritis activity in clinical
trials and clinical practice".)

● By contrast, structural damage is cumulative and irreversible. The degree of damage is closely
linked to inflammation and hence to disease activity, but is also associated with degeneration
and repair [43]. As structural damage progresses, the detection of variation in disease activity by
clinical examination becomes increasingly difficult. At these later stages, symptoms and signs of
inflammation, such as pain, stiffness, tenderness, swelling, and joint effusions, may be caused
either by continuing rheumatoid disease or as a secondary result of mechanical and
degenerative change.

Remission — Disease remission occurs when there is little or no evidence of clinical disease activity
(see below for criteria). However, achieving remission does not entirely preclude the development of
further erosive changes. This was illustrated in a retrospective study of 187 patients who were in
remission for six months and whose clinical course and radiographic findings were subsequently
followed [44]. A majority (52 percent) remained in remission during two years of follow-up. However,
despite inapparent clinically active disease, one new erosion in a previously unaffected joint
appeared in 14 percent of these patients.

In our experience, reaching remission is very rare without DMARDs. As an example, among 191
patients treated with such drugs beginning within a year of disease onset, 48 (25 percent) met
criteria for remission after three years of treatment, and 38 (20 percent) after five years of DMARD
therapy [45]. The likelihood of achieving a remission with DMARD treatment within the first year of
disease was greater in patients with less initial disease activity, less disability, lower levels of acute
phase reactants, absence of rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies
(ACPA), and less radiographic joint damage.

Attempts to define clinical remission for clinical practice and in clinical trials, in order to understand
better the natural history of RA and the effects of therapy, have resulted in provisional definitions of
remission by a joint effort of the American College of Rheumatology (ACR) and the European League
Against Rheumatism (EULAR) [46,47]. These definitions take into account that a complete lack of joint
pain, swelling, and tenderness may be impossible to achieve in patients who have developed
structural damage of the joints, despite actual remission in the rheumatoid disease process, and the
absence of all such symptoms and findings is not required by the ACR/EULAR criteria. (See
"Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on
'Remission'.)
The ACR/EULAR definitions of remission include use of either the Clinical Disease Activity Index (in
clinical practice) or the Simplified Disease Activity Index (for clinical trials). Alternatively, the definition
of remission for clinical practice can be met in patients with scores on the tender joint count, swollen
joint count, and patient global assessment (0-10 scale) all ≤1. The C-reactive protein (CRP) (in mg/dL)
is also included in the definition for use in clinical trials.

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Rheumatoid arthritis (The Basics)" and "Patient education:
Hand pain (The Basics)")

● Beyond the Basics topics (see "Patient education: Rheumatoid arthritis symptoms and diagnosis
(Beyond the Basics)" and "Patient education: Rheumatoid arthritis treatment (Beyond the Basics)"
and "Patient education: Complementary and alternative therapies for rheumatoid arthritis
(Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● The onset of rheumatoid arthritis (RA) is usually insidious, with the predominant symptoms
being pain, stiffness, and swelling of many joints. Typically, the metacarpophalangeal (MCP) and
proximal interphalangeal (PIP) joints of the fingers, the interphalangeal joints of the thumbs, the
wrists, and the metatarsophalangeal (MTP) joints of the toes are sites of arthritis early in the
disease. Other joints of the upper and lower limbs are also commonly affected. Onset may
occasionally be intermittent or with migratory joint involvement, or may be monoarticular. RA
may adversely affect a patient's capacity to perform the activities of daily living. (See 'Initial
clinical presentation' above and 'Typical 'classic' RA' above and 'Palindromic rheumatism' above
and 'Monoarthritis' above.)

● The key features of early rheumatoid inflammation are pain and swelling of the affected joints.
Painful inflammation is demonstrated either by local tenderness from pressure applied on the
joint or by pain on moving the joint. Swelling may be due to synovial hypertrophy or effusion.
Synovial thickening is detected by a "boggy" feel to a swollen joint, and effusion by
 demonstrating fluctuation. (See 'Symptoms and physical findings' above and 'Hands' above and
'Lower extremity' above and 'Axial skeleton' above and 'Cricoarytenoid joint' above.)

● RA eventually affects the peripheral joints in almost all patients. Involvement of axial and central
joints is less common, occurring in 20 to 50 percent of patients. Symmetrical joint involvement is
characteristic, although this may be less apparent early in the disease. The pattern of joint
involvement may also be diagnostically useful. Squeeze tenderness at the MCP and
metatarsophalangeal MTP joints and palpable synovial thickening at these joints are
characteristic of RA. (See 'Distribution of involved joints' above.)

● Extraarticular features of RA, including anemia, fatigue, subcutaneous ("rheumatoid") nodules,

pleuropericarditis, neuropathy, episcleritis, scleritis, splenomegaly, Sjögren's syndrome,
vasculitis, and renal disease, may occur during the course of the disease. (See 'Extraarticular
involvement' above and "Overview of the systemic and nonarticular manifestations of
rheumatoid arthritis".)

● A number of abnormalities are present in the blood and synovial fluid of patients with RA. These
include changes reflecting systemic and intraarticular inflammation, and the autoimmune
features of the disorder, including the presence of rheumatoid factors (RF) and anti-citrullinated
protein/peptide antibodies (ACPA). (See 'Laboratory findings' above.)

● Patients with RA develop joint space narrowing and bony erosions, which are best observed in
plain radiographs of the hands and feet. These may already be present when first seen by a
clinician but more usually become evident over time with ongoing synovitis beyond the first few
months of disease. (See 'Imaging' above.)

● RA shows a marked variation of clinical expression in individual patients ( table 1). This
difference may be apparent in the number and pattern of joint involvement and whether
extraarticular disease is prominent. Variation is also seen in the course of disease activity and the
rapidity of structural damage to joints. (See 'Clinical course' above and 'Patterns of progression'
above.)

● The concept of disease activity is based upon the state of the underlying inflammatory response,
and may be distinguished from the destructive process that leads to irreversible damage of the
joint ( table 2). Rarely, disease activity is absent; in this circumstance, the disease is said to be
in remission. (See 'Disease activity versus structural damage' above and 'Remission' above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like to acknowledge Ravinder N Maini, BA, MB BChir, FRCP,
FMedSci, FRS, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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